Megacities—urban areas with populations of ten million or greater—and other dense urban environments are emerging and growing globally, posing new challenges for U.S. military operations. The United States (U.S.) military can be better positioned for potential future operations within megacities as part of a joint, interagency, intergovernmental, and multinational team by increasing its understanding of megacity environments (Harris et al., 2014). Chemical exposures pose risk to the health and readiness of Service Members operating in these environments. The Naval Research Laboratory (NRL) prioritized a list of the top 30 chemicals of concern for global military operations based on physical characteristics and available toxicology data (Sutto, 2015). Occupational exposure to these chemicals increases risk of developing adverse health effects during mission operations or post-deployment. Policy guidelines specifying the use of the appropriate personal protective gear constitute the first line of defense to protect personnel by limiting exposure in the field. After a confirmed or suspected exposure event, far-forward diagnostic tools are needed to quickly and effectively determine and manage the risk of adverse health effects post-exposure in order to make informed command decisions about return-to-duty and treatment options. Identifying and quantifying biomolecular indicators in accessible biofluids such as blood, saliva, or urine is critically important for evaluating chemically-induced disease prognosis (Tawa et al., 2014; Ippolito et al., 2015). Biomarkers of end-organ toxicity can be integrated into a fieldable detection system to rapidly diagnose chemical exposure-induced adverse health effects in theater. Noninvasive or minimally invasive screening methods could enable early intervention, treatment, and informed decision making to optimize force readiness. Mapping biomolecular patterns of adverse health effects represents a promising solution to the complex problem of assessing health effects after exposure to mixtures of different chemicals and /or pollutants and aggregated exposure effects over time (Silins & Högberg, 2011).

This systematic literature review identifies and assesses the level of evidence for candidate far forward diagnostic technologies and biomarkers that may be used to detect emerging health effects from exposure to militarily-relevant chemicals. The review emphasizes a subacute exposure window (i.e., days to weeks) best suited to the short-term exposure scenarios anticipated in military operations and mission scenarios. Biomarker development demands meeting rigorous regulatory and clinical standards before adoption in the field, but military investment in this research and development process has the potential for significant returns in military healthcare during the deployment life cycle. Biomarker-based screening technologies can benefit routine health care screening, return-to-duty decision-making, triage during mass casualty exposure events, and/or guiding the development of diagnostics to inform treatment options. Biomarker-based far-forward diagnostic strategies and technologies have the potential to transform military healthcare in the changing face of warfare in megacities and dense urban operating environments

Methods

The peer-reviewed literature was surveyed to evaluate the weight-of-evidence regarding biomarkers for emerging health effects resulting from exposure to militarily-relevant chemicals (Table 1). The target list of militarily relevant chemicals was based on 30 prioritized megacity chemical hazards outlined in the NRL Industrial Chemical Assessment for Hazard, Probability, and Biomarker Prioritization (Sutto, 2015). A biomarker was defined as a molecular, cellular, or biophysical event linked to an emerging health effect.

Databases searched included PubMed, Web of Knowledge, Google Scholar, ClinicalTrials.gov, publicly available Department of Defense (DoD) technical reports (e.g., Defense Technical Information Center), non-DoD sources, and the Center for Disease Control Agency for Toxic Substance & Disease Registry and from the U.S. Library of Medicine Hazardous Substances Data Bank (“Agency for Toxic Substance & Disease Registry - Medical Management Guidelines Home Page,” n.d., “U.S. National Library of Medicine - Hazardous Substances Data Bank,” n.d.). Search terms were selected to identify studies that examined health effects associated with exposure to the high priority chemicals. The search was limited to articles published in English from January 2005 to May 2015.

An objective two-step grading approach based on the U.S. Preventive Services Task Force Grade Definitions was used to assess the internal validity of individual studies published in peer-reviewed journal articles that met the inclusion criteria. The first step in evidence grading methodology identified and ranked the study design within a hierarchy of evidence, and the second step assessed the study quality (good, fair, poor). Study designs included the following categories: preclinical research (e.g., animal models), clinical research (e.g., clinical trials, diagnostic studies), epidemiological research (e.g., cohort studies, intervention studies), and secondary research (e.g., meta-analysis, systematic reviews). If a publication contained both a preclinical study and a clinical study, a separate grade was assigned for each study.

Results and Discussion

A review of 57 current papers in the diagnostic device literature identified five classes of biomarker detection devices (Figure 1). Most of the devices in development are lab-on-a-chip designs and paper-based lab-on-a-chip (LOC paper) protoypes. Frequently portable and disposable, these designs may be amenable to military field settings (Shafiee et al., 2015). Unique technological challenges limit the utility of many prototype diagnostics for use in a far-forward operational setting. Further research, clinical trials, and validation are needed to advance the devices beyond the prototype stage (Hoenigl et al., 2014). Ruggedization and miniaturization of laboratory prototypes are significant challenges in fielding these devices (Greenwood et al., 2007).

Table 2 lists the target organs of adverse health effects following exposure to each of the chemicals. Table 3 reports the key acute, subacute, and chronic health effects for each target organ. Most of the data summarized in Tables 2 and 3 are derived from a scan of public toxicology data repositories (e.g., the Hazardous Substances Data Bank and related ToxNet resources). These repositories identify relevant studies outside the time frame of the systematic review (i.e., before 2005-2015).

As megacities and dense urban environments continue to grow in number and population size, there is an unmet need to understand the health threats of service members exposed to toxic chemicals and environmental hazards unique to the megacity operational environment. Properly validated biomarkers of exposure and effect can integrate with current biomonitoring systems throughout the soldier deployment life cycle to inform medical decisions during and after exposure events, especially in polluted megacity operational environments with increased risk of non-agent chemical exposure. Further research is needed to ensure the fieldability of ruggedized detection systems in the megacity environment.

Acknowledgements: This manuscript is based on a DTIC report submitted by Booz Allen Hamilton entitled “Biomarkers for Health Effects of Industrial Chemical Exposure Literature Review”, submitted to USACEHR on behalf of USAMRMC-MOMRP on 26 June 2015. We gratefully acknowledge COL Thomas C. Timmes, USA, Commander of USACEHR, for programmatic support.

The views, opinions, and/or findings contained in this report are those of the author and should not be construed as official Department of the Army position, policy, or decision, unless so designated by other official documentation.

About the Author(s)

Danielle L. Ippolito, Ph.D., is a Research Physiologist and Task
Area Manager for the US Army Center for Environmental Health Research
(USACEHR). She is a biomedical researcher with nearly 10 years of Army
experience in clinical and laboratory research environments at Fort Detrick
and Madigan Army Medical Center (Joint-Base Lewis McChord). She uses an
integrative systems biology approach to develop medical diagnostics and
decision aids that protect Warfighters from chemical threats in hostile
operational environments.